Gene Finding May Lead to Better Understanding of Birth Defects

Human Disorder Found to be Due to Alteration in a Developmental Pathway Intensly Studied in Simpler Organisms

July 1997

BETHESDA, Md. - Scientists at the National Human Genome Research Institute (NHGRI), reported recently that a newly discovered gene that causes a rare childhood disease marked by a wide range of birth defects may be an important key to other human developmental disorders. A mutation in the gene-known as JAG1-causes Alagille syndrome. NHGRI Director Dr. Francis Collins, visiting scientist Dr. Settara Chandrasekharappa, postdoctoral fellow Dr. Takaya Oda, and their colleagues report their finding in a recent issue of the journal Nature Genetics. The disease, also known as AGS, is characterized by abnormalities of the liver, heart, eye and vertebrae, as well as certain facial features.

Working with researchers at Nagoya City University in Japan, the Children's Hospital of Philadelphia, and Research Genetics Inc. of Huntsville, Alabama, Collins and Chandrasekharappa observed that JAG1, located on Chromosome 20, is mutated in individuals with AGS. JAG1 produces a molecule that resides on the cell surface interacts with the products of the so-called NOTCH family of genes, which also reside on cell surfaces. Based on extensive work done on similar genes in fruitflies and roundworms, scientists believe that signalling between these proteins is critical for the proper development of embryos. Individuals with AGS are born with one copy of JAG1 not functioning. Even though the remaining copy is normal, without the right dosage of JAG1 in their genetic makeup, AGS is the result.

"In the context of these observations, it would not be surprising if other disorders of human development turn out to be caused by dosage abnormalities of other members of the family of Notch proteins and Notch ligands," the researchers write in Nature Genetics.

"Now that the gene has been identified," says Collins, "we can anticipate both advances in understanding of the human disorder, and progress in basic understanding of human development, aided by this new connection between molecule and phenotype."

AGS afflicts approximately one out of every 70,000 children born in the United States. The disorder varies greatly in severity. Some affected children appear almost normal, while others suffer from jaundice and liver failure and may require organ transplantation.

"It is very important to note that the gene discovery will significantly improve the ability to diagnose this often-missed disorder. In two of our families, individuals not thought to be affected (but who had not undergone thorough clinical investigation) turned out to carry the same alteration as a more obviously affected relative," says Dr. Chandrasekharappa.